Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/16—Macromolecular materials obtained by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/14—Macromolecular materials
  • A61L27/18—Macromolecular materials obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/36—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix
  • A61L27/38—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells
  • A61L27/3839—Materials for grafts or prostheses or for coating grafts or prostheses containing ingredients of undetermined constitution or reaction products thereof, e.g. transplant tissue, natural bone, extracellular matrix containing added animal cells characterised by the site of application in the body
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L27/00—Materials for grafts or prostheses or for coating grafts or prostheses
  • A61L27/50—Materials characterised by their function or physical properties, e.g. injectable or lubricating compositions, shape-memory materials, surface modified materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2400/00—Materials characterised by their function or physical properties
  • A61L2400/06—Flowable or injectable implant compositions
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2430/00—Materials or treatment for tissue regeneration
  • A61L2430/34—Materials or treatment for tissue regeneration for soft tissue reconstruction

Definitions

• the present disclosure relates to soft-tissue fillers, to compositions for forming soft-tissue fillers, and to methods of administering soft-tissue fillers to patients.
• Injectable soft-tissue fillers can provide a noninvasive option for reducing skin defects, such as wrinkles, lines, other volume loss due to the natural effects of aging, or scars, to enhance fullness of the lips or act as a spacer between skin and organs or between two organs.
• biopolymers such as collagen or hyaluronic acid.
• Such biopolymers while generally being well tolerated, cause allergic responses to them in some patients.
• biopolymers are also generally of high molecular weight, resulting in solutions having high intrinsic viscosity.
• non-biologically-derived hydrophilic polymers By employing non-biologically-derived hydrophilic polymers as an alternatives, there is potential for compositions having reduced immune responses, and thus reduced risk of allergic reactions. Moreover, non-biologically-derived hydrophilic polymers which are crosslinked in vivo offer the potential for formulations that are injected at low molecular weight and thus low viscosity, requiring low extrusion force for injection and making them straightforward to deploy to a patient using a thin gauge needle.
• the present disclosure pertains to injectable in vivo crosslinking materials for use as soft tissue fillers that comprise (a) a reactive multi-arm polymer that comprises a plurality of hydrophilic polymeric arms, at least a portion of the hydrophilic polymeric arms comprising one or more reactive end groups and (b) a multifunctional compound that comprises functional groups that are reactive with the reactive end groups of the reactive multi-arm polymer.
• the hydrophilic polymeric arms may comprise one or more hydrophilic monomers.
• the hydrophilic polymeric arms may comprise one or more monomers selected from N-vinyl pyrrolidone, ethylene oxide, hydroxyethyl acrylate, hydroxyethyl methacrylate, PEG methyl ether acrylate or PEG methyl ether methacrylate.
• the hydrophilic polymeric arms may further comprises a hydrolysable ester group.
• the reactive end groups may be electrophilic groups and the functional groups may be nucleophilic groups.
• the reactive end groups may be selected from N- hydroxysuccinimide esters, imidazole esters, imidizole carboxylates and benzotriazole esters.
• the functional groups may be selected from amine groups and thiol groups.
• the multifunctional compound may comprise a polyamine.
• the reactive end groups of the reactive multi-arm polymer and the functional groups of the multifunctional compound react with one another via an amide coupling reaction.
• the reactive end groups of the reactive multi-arm polymer comprise carboxyl groups
• the functional groups of the multifunctional compound comprise amine groups
• the in vivo crosslinking material further comprises a carbodiimide coupling agent, such as l-ethyl-3-(3- dimethylaminopropyl)carbodiimide (EDC) among others.
• the present disclosure pertains to systems for forming injectable in vivo crosslinking materials in accordance with any of the above aspects and embodiments, which comprise (a) a first composition comprising the reactive multi-arm polymer and (b) a second composition comprising the multifunctional compound.
• the first composition, the second composition, or both the first composition and the second composition may comprise a therapeutic agent, an imaging agent, or both.
• the system may comprise a first syringe barrel containing the first composition and a second first syringe barrel containing the second composition.
• the system further comprises a delivery device configured to deliver a mixture of the first composition and the second composition into epidermis, dermis, and/or subcutaneous tissue of a patient.
• the delivery device comprises a first reservoir containing the first composition and a second reservoir containing the second composition and/or the delivery device comprises a needle that is configured to inject the injectable in vivo crosslinking material into epidermis, dermis, and/or subcutaneous tissue of a patient.
• the present disclosure pertains to methods comprising injecting an injectable in vivo crosslinking material in accordance with any of the above aspects and embodiments into epidermis, dermis, and/or subcutaneous tissue of a patient.
• the injectable in vivo crosslinking material is injected beneath a skin defect that is lower or deeper than surrounding skin and/or thein vivo crosslinking material is molded by a healthcare within the patient after injection.
• FIG. 1 is a schematic illustration of a method of crosslinking a reactive multi-arm polymer with a multifunctional compound, in accordance with an embodiment of the present disclosure.
• the present disclosure pertains to injectable in vivo crosslinking materials for use as soft tissue fillers, to compositions for forming such injectable in vivo crosslinking materials, and to methods of using such compositions.
• the injectable in vivo crosslinking materials of the present disclosure comprise a reactive multi-arm polymer, a multifunctional compound that comprises functional groups that are reactive with the reactive multi-arm polymer and, optionally, one or more additional agents such as therapeutic agents and/or contrast agents, among other possibilities.
• the multi-arm polymers for use in the present disclosure comprise a plurality of polymeric arms (e.g., having two, three, four, five, six, seven, eight, nine, ten or more arms). At least a portion of the total polymeric arms in the injectable in vivo crosslinking material (e.g., ranging from 1% to 2.5% to 5% to 10% to 25% to 50% or 75% to 90% to 95% to 97.5% to 99% to 100% of the polymeric arms) comprise one or more reactive end groups.
• the polymeric arms are hydrophilic polymeric arms.
• Such hydrophilic polymeric arms which may be composed of any of a variety of synthetic, natural, or hybrid synthetic-natural polymers including, for example, poly(alkylene oxides) such as poly(ethylene oxide) (also referred to as PEG), polypropylene oxide) or poly(ethylene oxide-co-propylene oxide), poly(vinylpyrrolidone), poly(vinyl alcohol), poly(allyl alcohol), poly(ethyleneimine), poly(allylamine), poly(vinyl amine), polyoxazolines including poly(2-alkyl-2-oxazolines) such as poly(2-methyl-2-oxazoline), poly(2-ethyl-2-oxazoline) and poly(2-propyl-2- oxazoline), poly(amino acids), polysaccharides, and combinations thereof.
• poly(alkylene oxides) such as poly(ethylene oxide) (also referred to as PEG), polypropylene oxide) or poly(ethylene oxide-co-propylene oxide), poly(vinylpyrrolidone
• the polymeric arms extend from a core region.
• the core region comprises a residue of a polyol that is used to form the polymeric arms.
• Illustrative polyols may be selected, for example, from straight-chained, branched and cyclic aliphatic polyols including straight-chained, branched and cyclic polyhydroxyalkanes, straight-chained, branched and cyclic polyhydroxy ethers, including polyhydroxy polyethers, straight-chained, branched and cyclic polyhydroxyalkyl ethers, including polyhydroxyalkyl polyethers, straight-chained, branched and cyclic sugars and sugar alcohols, such as glycerol, mannitol, sorbitol, inositol, xylitol, quebrachitol, threitol, arabitol, erythritol, adonitol, dulci
• Illustrative polyols also include aromatic polyols including l,l,l-tris(4'-hydroxyphenyl) alkanes, such as l,l,l-tris(4- hydroxyphenyl)ethane, and 2,6-bis(hydroxyalkyl)cresols, among others.
• the polyol is an oligomer of a sugar alcohol such as glycerol, mannitol, sorbitol, inositol, xylitol, or erythritol, among others.
• the polyol may contain three or more hydroxyl groups, for example, between four and twelve hydroxyl groups in certain cases.
• the reactive end groups are selected from electrophilic groups and nucleophilic groups.
• the reactive groups may be electrophilic groups selected from imidazole esters, imidazole carboxylates, benzotriazole esters, and imide esters, including N-hydroxysuccinimidyl esters.
• a particularly beneficial electrophilic reactive group is an N-hydroxysuccinimidyl ester group.
• the reactive groups may be nucleophilic groups selected from amine groups and/or thiol groups.
• a reactive multi-arm polymer may be formed by reacting (a) a polymer that comprises a core (e.g., a polyol residue core, among others) and a plurality of polymeric arms, at least a portion of which are terminated in one or more hydroxyl groups with (b) a cyclic anhydride (e.g., glutaric anhydride, succinic anhydride, malonic anhydride, etc.) to form a reaction product in the form of a polymer that comprises the core and the plurality of polymeric arms, at least a portion of which polymeric arms are terminated in a moiety that comprises a carboxylic acid group and a hydrolysable ester group positioned between the carboxylic acid group and the polymeric arm.
• a cyclic anhydride e.g., glutaric anhydride, succinic anhydride, malonic anhydride, etc.
• this reaction product may be treated with a coupling agent (e.g., a carbodiimide coupling agent such as N,N'-dicydohexylcarbodiimide (DCC), l-Ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC), N-Hydroxybenzotriazole (HOBt), BOP reagent, and/or another coupling agent) and N-hydroxysuccinimde (NHS), to yield a reactive multi-arm polymer comprising succinimidyl end groups, in particular, a reactive multi-arm polymer that comprises a core and a plurality of polymeric arms, at least a portion of which comprise a moiety that comprises a hydrolysable ester group and a succinimide ester group.
• a coupling agent e.g., a carbodiimide coupling agent such as N,N'-dicydohexylcarbodiimide (DCC),
• the polymeric arms are formed by polymerization of at least one type of monomer from a suitable multifunctional initiator molecule.
• the multifunctional initiator molecule may a polyol.
• a polyol specifically, a polyol having eight hydroxyl groups such as tripentaerythritol, may be used as an initiator for reaction in which a cyclic alkylene oxide, specifically, ethylene oxide, is polymerized in the presence of the polyol initiator and a catalyst, for example, a strong base such as butyl lithium or potassium t-butoxide, to form a polymer in which eight polyalkylene oxide arms extend from a polyol residue core.
• the terminal hydroxyl groups are then converted to succinimidyl glutarate groups using glutaric anhydride and N-hydroxysuccinide as reagents.
• reactive multi-arm polymers e.g., one having 2, 3, 4, 5, 6, 7, 8, 9, 10 or more arms
• reactive multi-arm polymers may be formed, which comprise a core and a plurality of hydrophilic polymeric arms extending from the core, wherein at least a first portion of the polymeric arms each comprises one or more reactive end groups.
• Reactive multi-arm polymers in accordance with the present disclosure may be water soluble.
• a reactive multi-arm polymer in accordance with the present disclosure may be combined with a suitable multifunctional compound to form a soft tissue filler that is crosslinkable in vivo.
• a reactive multi-arm polymer in accordance with the present disclosure may be crosslinked with a multifunctional compound having functional groups that are reactive with the reactive groups of the multi-arm polymer.
• the functional groups of the multifunctional compound may be nucleophilic groups and the reactive groups of the multi-arm polymer may be electrophilic groups.
• the functional groups of the multifunctional compound may be electrophilic groups and the reactive groups of the reactive multi-arm polymer may be nucleophilic groups.
• the reactive groups of the reactive multi-arm polymer and the functional groups of the multifunctional compound react with one another via an amide coupling reaction.
• the functional groups of the multifunctional compound may be nucleophilic groups selected from amine groups and thiol groups.
• the functional groups of the multifunctional compound may be electrophilic groups selected from imidazole esters, imidazole carboxylates, benzotriazole esters, and imide esters, including N-hydroxysuccinimidyl esters.
• the multifunctional compound may be a polyamine.
• polyamines suitable for use in the present disclosure include, for example, small molecule polyamines (e.g., containing at least two amine groups, for instance, from 3 to 20 amine groups, in some embodiments), comb polymers having amine side groups, and branched polymers having amine end groups, including dendritic polymers having amine end groups.
• multifunctional amines which may be used as the multifunctional compound include trilysine, ethylenetriamine, diethylene triamine, hexamethylenetriiamine, di(heptamethylene) triamine, di(trimethylene) triamine, bis(hexamethylene) triamine, triethylene tetramine, tripropylene tetramine, tetraethylene pentamine, hexamethylene heptamine, pentaethylene hexamine, dimethyl octylamine, and dimethyl decylamine, and JEFFAMINE polyetheramines available from Huntsman Corporation, among others.
• multifunctional amines include polypeptides including poly(L-lysine), chitosan, and poly(allyl amine), among others.
• the multi-arm polymers having hydrophilic polymeric arms that comprise carboxyl end groups can be reacted with a coupling agent, for example, a carbodiimide coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC) to form an O-acylisourea intermediate, which in turn reacts with amine groups to form amide linkages in vivo.
• a coupling agent for example, a carbodiimide coupling agent such as l-ethyl-3-(3-dimethylaminopropyl)carbodiimide (EDC)
• EDC l-ethyl-3-(3-dimethylaminopropyl)carbodiimide
• injectable in vivo crosslinking materials for use as soft tissue fillers are formed by combining a first composition comprising a reactive multiarm polymer like that described above (e.g., a first fluid composition comprising the reactive multi-arm polymer or a first dry composition that comprises the multi-arm polymer, to which a suitable fluid such as water for injection, saline, etc. can be added to form a first fluid composition) and (b) a second composition comprising a multifunctional compound like that described above (e.g., a second fluid composition comprising the multifunctional compound, or a second dry composition that comprises the multifunctional compound, to which a suitable fluid such as water for injection, saline, etc. can be added to form a second fluid composition).
• a first composition comprising a reactive multiarm polymer like that described above
• a second composition comprising a multifunctional compound like that described above
• a second fluid composition comprising the multifunctional compound, or a second dry composition that comprises the multifunctional compound, to which a suitable fluid such
• a reactive multi-arm polymer 110 having a core 110c, arms 110a and reactive end groups HOe like that described herein may be crosslinked with a multifunctional compound 120 like that described herein (e.g., a polyamine such as trilysine) to form a crosslinked product 130.
• a multifunctional compound 120 like that described herein (e.g., a polyamine such as trilysine) to form a crosslinked product 130.
• the first composition may further comprise, for example, additional agents such as therapeutic agents and/or contrast agents, among other possibilities.
• the second composition may further comprise, for example, additional agents such as therapeutic agents and/or contrast agents, among other possibilities.
• the injectable in vivo crosslinking materials for use as soft tissue fillers of the present disclosure may be delivered to the epidermis, dermis, and/or subcutaneous tissue (also called the hypodermis) of a patient a suitable delivery device.
• the injectable in vivo crosslinking materials may be used delivered in or between organs.
• the delivery device may include a needle, one or more reservoirs (e.g., one or more syringe barrels), and one or more actuators for expelling the contents of the the one or more reservoirs (e.g., one or more plungers).
• one or more reservoirs e.g., one or more syringe barrels
• one or more actuators for expelling the contents of the the one or more reservoirs e.g., one or more plungers.
• the delivery device may comprise a first reservoir that contains a first fluid composition comprising a reactive multi-arm polymer like that described above (or a first dry composition to which a suitable fluid can be added to form a first fluid composition) and a second reservoir that contains a second fluid composition comprising a multifunctional compound like that described above (or a second dry composition to which a suitable fluid such as water for injection, saline, etc. can be added to form the second fluid composition).
• the first and second fluid compositions are dispensed from the first and second reservoirs, whereupon the first and second fluid compositions interact and crosslink with one another.
• the system may include a delivery device that comprises a double-barrel syringe, which includes first barrel having a first barrel outlet containing the first composition, a second barrel having a second barrel outlet containing the second composition, a first plunger that is movable in the first barrel, and a second plunger that is movable in the second barrel.
• a delivery device that comprises a double-barrel syringe, which includes first barrel having a first barrel outlet containing the first composition, a second barrel having a second barrel outlet containing the second composition, a first plunger that is movable in the first barrel, and a second plunger that is movable in the second barrel.
• the device may further comprise a mixing section having a first mixing section inlet in fluid communication with the first reservoir (e.g., in fluid communication with the first barrel outlet), a second mixing section inlet in fluid communication with second reservoir (e.g., in fluid communication with the second barrel outlet), and a mixing section outlet in fluid communication with a needle.
• a mixing section having a first mixing section inlet in fluid communication with the first reservoir (e.g., in fluid communication with the first barrel outlet), a second mixing section inlet in fluid communication with second reservoir (e.g., in fluid communication with the second barrel outlet), and a mixing section outlet in fluid communication with a needle.
• the first and second fluid compositions are dispensed from the first and second barrels, whereupon the first and second fluid compositions interact and form an injectable material, which is administered tissue of a subject, and which subsequently crosslinks in vivo to act as a soft tissue filler.
• the first and second fluid compositions may pass from the first and second barrels, into the mixing section via first and second mixing section inlets, whereupon the first and second fluid compositions are mixed to form an admixture, which admixture exits the mixing section via the mixing section outlet and enters a needle, from which the admixture can be injected into a patient.
• the present disclosure pertains to crosslinked products that are implanted in tissue, in particular, crosslinked products of (a) a reactive multi-arm polymer as described herein and (b) a multifunctional compound as described herein, which are implanted in one or more of epidermis, dermis, or subcutaneous tissue.
• injectable in vivo crosslinking materials for use as soft tissue fillers in accordance with the present disclosure may be formed by mixing a first fluid composition comprising a reactive multi-arm polymer as described herein with a second composition comprising a multifunctional compound as described herein and injecting the mixture into one or more of epidermis, dermis, or subcutaneous tissue.
• the injectable in vivo crosslinking materials may be formed by mixing a first fluid composition comprising a reactive multi-arm polymer as described herein with a second composition comprising a multifunctional compound as described herein and injecting the mixture into or between organs.
• the crosslinking rate of the mixture may be tuned to allow a healthcare provider who is administering the compositions sufficient time to mold the mixture after it is injected, thereby maximizing the aesthetic effect of the mixture, before the mixture crosslinks to a point where further molding of the mixture is prevented.
• a crosslinking rate of the mixture may be such that the mixture is moldable for several minutes after the mixture is formed, after which further molding is prevented due to the degree of crosslinking that has occurred.
• the rate of crosslinking may be controlled through control of pH, for example, using suitable pH buffers, among other approaches.
• the extent of crosslinking for a given material can be assessed, for example, by monitoring changes in the elastic modulus of the material, which can be measured using a rheometer can be used.
• dynamic mechanical analysis can be used to measure the storage modulus (G and the loss modulus (G'O of a given material as a function of time and the variation of G' and G" in time can indicate the extent of the curing reaction.
• the crosslinking rate of the mixture can be such that an onset of cure occurs within a time period ranging from 1 minute to 10 minutes and/or such that full cure (e.g., 95% of the final stiffness) is achieved within a time period ranging from 30 minutes to 1 hour, among other possibilities.
• Injectable in vivo crosslinking materials for use as soft tissue fillers as described herein may contain one or more additional agents.
• imaging agents include (a) fluorescent dyes such as fluorescein, indocyanine green, or fluorescent proteins (e.g . green, blue, cyan fluorescent proteins), (b) contrast agents for use in conjunction with magnetic resonance imaging (MRI), including contrast agents that contain elements that form paramagnetic ions, such as Gd (III) , Mn (II) , Fe (III) and compounds (including chelates) containing the same, such as gadolinium ion chelated with diethylenetriaminepentaacetic acid, (c) contrast agents for use in conjunction with ultrasound imaging, including organic and inorganic echogenic particles (/a, particles that result in an increase in the reflected ultrasonic energy) or organic and inorganic echolucent particles ( .a, particles that result in a decrease in the reflected ultrasonic energy), (d) contrast agents for use in connection with x-ray fluoroscopy, including metals and metal compounds ⁇

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• 2021
  • 2021-02-02 WO PCT/US2021/016213 patent/WO2021158546A1/en unknown
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